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Vitamin K- An overview

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Vitamin K- chemistry, metabolism, deficiency and vitamin K antagonists

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Vitamin K- An overview

  1. 1. Professor (Dr. )Namrata Chhabra 27-Jan-18 1Biochemistry for medics- Lecture Notes- Namrata Chhabra
  2. 2. Learning objectives To understand: 1) Chemistry, and metabolism of vitamin K 2) Biological significance, 3) Vitamin K deficiency -Causes, and clinical implications 4) Mechanism of action of vitamin K antagonists 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 2
  3. 3. Vitamin K  Vitamin K represents a group of lipophilic and hydrophobic vitamins.  Originally identified for its role in the process of blood clot formation  ("K" is derived from the German word "koagulation") 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 3
  4. 4. Vitamin K-Family  Three compounds have the biological activity of vitamin K  Phylloquinone (Vitamin K1), the normal dietary source, found in green vegetables  Menaquinones (vitamin K2), synthesized by intestinal bacteria, with differing lengths of side chain;  and Menadione and menadiol diacetate, synthetic compounds that can be metabolized to phylloquinone. 27-Jan-18 4Biochemistry for medics- Lecture Notes- Namrata Chhabra
  5. 5. Vitamin K-Chemistry 27-Jan-18 5 Phylloquinone have a 20 C side chain , Menaquinones have a 30 C side chain. The synthetic vitamin K (menadione, menadiol diacetate) have only hydrogen in place of isoprenoid side chain that makes these vitamin water-soluble. Naphthoquinone ring Isoprenoid side chain
  6. 6. Dietary Sources  Green leafy vegetables such as kale and spinach,  Margarine and liver.  Vegetable oils and particularly olive, canola, and soybean oils.  Some amount is contributed by intestinal bacteria 27-Jan-18 6Biochemistry for medics- Lecture Notes- Namrata Chhabra
  7. 7. Absorption, Transportation and Storage  Absorption takes place in small intestine in the presence of bile salts.  The transportation from intestine is carried out through chylomicrons.  Storage occurs in liver and from liver transportation to peripheral cells is carried out bound with beta lipoproteins (VLDL). 27-Jan-18 7Biochemistry for medics- Lecture Notes- Namrata Chhabra
  8. 8. Conditions causing impaired absorption of vitamin K  Fat malabsorption is associated with impaired absorption of vitamin K and other fat soluble vitamins. 27-Jan-18 8Biochemistry for medics- Lecture Notes- Namrata Chhabra
  9. 9. Impaired absorption of vitamin K 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 9 Absorption of vitamin K may also be decreased by mineral oil, bile acid sequestrants (Cholestyramine, Colestipol) and Orlistat (weight loss medication).
  10. 10. Recommended daily allowance (RDA)  The average daily allowance is 50-120 mcg/day.  Requirement increases in –  Liver disorders  Patients on prolonged antibiotic therapy, bile acid sequestrants (Cholestyramine, colestipol) and Orlistat (weight loss medication) 27-Jan-18 10Biochemistry for medics- Lecture Notes- Namrata Chhabra
  11. 11. Functions of Vitamin K Coagulation Bone Synthesis Prevention of atherosclerosis 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 11
  12. 12. Mechanism of action of vitamin K  Vitamin K has an important role in post- translational modification of calcium binding proteins  Vitamin K-dependent gamma-carboxylation occurs only on specific glutamic acid residues in a small number of vitamin K-dependent proteins, it is critical to the calcium-binding function of those proteins. 27-Jan-18 12Biochemistry for medics- Lecture Notes- Namrata Chhabra Glutamic acid
  13. 13. Vitamin K-dependent gamma-carboxylation 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 13 Vitamin K acts as a cofactor for Carboxylase enzyme that catalyzes the carboxylation glutamic acid, resulting in its conversion to gamma-carboxy glutamic acid (Gla).
  14. 14. 1) Role of vitamin K in coagulation  Factors II (prothrombin), VII, IX, and X make up the core of the coagulation cascade.  These factors are synthesized in the liver in the inactive form.  They undergo post translational modifications, gamma carboxylation of glutamic acid residues. 27-Jan-18 14Biochemistry for medics- Lecture Notes- Namrata Chhabra
  15. 15. Role of vitamin K in coagulation  Gamma carboxylation imparts another negative charge to promote the effective binding of these factors/proteins to calcium ions.  γ-Carboxyglutamates by chelating calcium ions, therefore, permit the binding of the blood clotting proteins to membranes.  Prothrombin and several other proteins of the blood clotting system (Factors VII, IX, and X, and proteins C and S) each contain 4–6 γ- carboxyglutamate residues. 27-Jan-18 15Biochemistry for medics- Lecture Notes- Namrata Chhabra
  16. 16. 27-Jan-18 16
  17. 17. Vitamin K cycle  Vitamin K is a fat-soluble vitamin, the body stores very little of it, and its stores are rapidly depleted without regular dietary intake.  Because of its limited ability to store vitamin K, the body recycles it through a process called the vitamin K cycle.  The vitamin K cycle allows a small amount of vitamin K to function in the gamma-carboxylation of proteins many times, decreasing the dietary requirement. 27-Jan-18 17Biochemistry for medics- Lecture Notes- Namrata Chhabra
  18. 18. Vitamin K cycle  Reduced lipoamide is required for the activity of Epoxide reductase and NADPH is needed for the action of vitamin K reductase. 27-Jan-18 18Biochemistry for medics- Lecture Notes- Namrata Chhabra
  19. 19. Vitamin K Antagonists  Dicumarol and Warfarin, inhibit coagulation through antagonism of the action of vitamin K.  These are competitive inhibitor of Epoxide reductase.  By preventing recycling of vitamin K inhibiting two important reactions , these drugs create a functional vitamin K deficiency  In the presence of Warfarin, vitamin K epoxides cannot be reduced, they accumulate and are excreted. 27-Jan-18 19Biochemistry for medics- Lecture Notes- Namrata Chhabra
  20. 20. Role of vitamin K in blood coagulation 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 20
  21. 21. Indications for using vitamin K antagonists  The main indications for a patient to receive vitamin K antagonists (VKAs) are the following:  Mechanical Heart Valves  Atrial Fibrillation  Deep Vein Thrombosis and Pulmonary Embolism  Myocardial infarction  Acute Ischemic Stroke The pathological formation of a blood clot, or thrombosis, poses significant health risks in such patients 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 21
  22. 22. Some facts about Vitamin K Antagonists  Large quantities of dietary or supplemental vitamin K can overcome the anticoagulant effect of vitamin K antagonists  The major side effect of Warfarin is bleeding. INR (international normalized ratio-a laboratory measurement of how long it takes blood to form a clot) is used to determine the effects of oral anticoagulants on the clotting system.  In healthy people an INR of 1.1 or below is considered normal. An INR range of 2.0 to 3.0 is generally an effective therapeutic range for people taking warfarin. 27-Jan-18 22Biochemistry for medics- Lecture Notes- Namrata Chhabra
  23. 23. 2) Synthesis of Bone  Vitamin K is also important in synthesis of two proteins that contain γ- carboxyglutamate that are present in bone- osteocalcin and bone matrix Gla protein.  Osteocalcin is a protein synthesized by osteoblasts.  The synthesis of osteocalcin by osteoblasts is regulated by the active form of vitamin D, 1,25(OH)2D3 or calcitriol.  The mineral-binding capacity of osteocalcin requires vitamin K- dependent gamma-carboxylation of three glutamic acid residues. 27-Jan-18 23Biochemistry for medics- Lecture Notes- Namrata Chhabra
  24. 24. Synthesis of Bone Calcium-Binding Proteins After gamma carboxylation osteocalcein binds tightly to calcium. 27-Jan-18 24Biochemistry for medics- Lecture Notes- Namrata Chhabra Treatment of pregnant women with Warfarin can lead to fetal bone abnormalities (Fetal Warfarin syndrome)
  25. 25. Synthesis of Bone Calcium-Binding Proteins  Matrix Gla protein- MGP has been found in bone, cartilage, and soft tissue, including blood vessels. MGP prevents the calcification of soft tissues and cartilages, while facilitating normal bone growth and development.  Protein S- The vitamin K-dependent anticoagulant protein S is also synthesized by osteoblasts, but its role in bone metabolism is unclear. Children with inherited protein S deficiency suffer complications related to increased blood clotting as well as decreased bone density. 27-Jan-18 25Biochemistry for medics- Lecture Notes- Namrata Chhabra
  26. 26. Vitamin K deficiency 27-Jan-18 26Biochemistry for medics- Lecture Notes- Namrata Chhabra Vitamin K deficiency Dietary deficiency Fat malabsorption Surgical interventions of intestine Chronic liver diseases Prolonged intake of antibiotics
  27. 27. Vitamin K deficiency in the newborn 27-Jan-18 27Biochemistry for medics- Lecture Notes- Namrata Chhabra Maternal medication Anticonvuls ants Antibiotics Antitubercul ar drugs Vitamin K antagonists Newborn Vitamin K deficiency Maternal medication Inadequate placental transfer Limited storage in liver Inadequate availability in breast milk
  28. 28. Clinical Manifestations  The main symptom is bleeding (hemorrhage)—into the skin (causing bruises), from the nose, from a wound, in the stomach, or in the intestine.  Blood may be seen in the urine or stool.  In newborns, life-threatening bleeding within or around the brain may occur. 27-Jan-18 28Biochemistry for medics- Lecture Notes- Namrata Chhabra
  29. 29. Hallmarks of vitamin K deficiency 27-Jan-18 29Biochemistry for medics- Lecture Notes- Namrata Chhabra Weak bones
  30. 30. Laboratory Studies A Prothrombin time (PT) Activated partial Thromboplastin time (aPTT), Fibrinogen levels, and  A platelet count can be included in the initial workup for vitamin K deficiency bleeding (VKDB) in a newborn. Full coagulation profile 27-Jan-18 30Biochemistry for medics- Lecture Notes- Namrata Chhabra
  31. 31. Laboratory Studies A prolonged PT is usually the first laboratory test result to be abnormal in vitamin K deficiency bleeding due to reduction in Prothrombin, FVII, FIX, and FX levels. 27-Jan-18 31Biochemistry for medics- Lecture Notes- Namrata Chhabra
  32. 32. Laboratory studies  Patients with liver disease may have an elevated prothrombin time because of liver cell destruction as well as vitamin K deficiency.  If an elevated prothrombin time does not improve on vitamin K therapy, it can be deduced that it is not the result of vitamin K deficiency. 27-Jan-18 32Biochemistry for medics- Lecture Notes- Namrata Chhabra
  33. 33. Treatment of vitamin K deficiency  For patients with chronic malabsorption, 1–2 mg/d of vitamin K should be given orally,  or 1–2 mg/week can be taken parenterally. 27-Jan-18 33Biochemistry for medics- Lecture Notes- Namrata Chhabra
  34. 34. Treatment A vitamin K injection in the muscle is recommended for all newborns to reduce the risk of bleeding within the brain after delivery. 27-Jan-18 34Biochemistry for medics- Lecture Notes- Namrata Chhabra
  35. 35. Toxicity  Toxicity from dietary phylloquinone and menaquinones has not been described.  High doses of vitamin K can impair the actions of oral anticoagulants. 27-Jan-18 35Biochemistry for medics- Lecture Notes- Namrata Chhabra
  36. 36. Summary  Vitamin K is a fat soluble vitamin  Phylloquinone, Menaquinone and Menadione are the members of vitamin K family  Vitamin K acts as a coenzyme for the gamma carboxylation of glutamic residues of Calcium binding proteins  Plays an important role in blood clotting, bone formation and prevention of calcification of soft tissues  Deficiency of vitamin K is manifested in the form of bleeding tendencies and hemorrhages  Oral or injectable vitamin K can be recommended depending upon the severity of the disease. 27-Jan-18 36Biochemistry for medics- Lecture Notes- Namrata Chhabra
  37. 37. Further reading  http://www.namrata.co/vitamin-k-chemistry-and-functions-part-1/  http://www.namrata.co/category/vitamins/theory-notes-vitamins/  http://www.namrata.co/vitamin-k-chemistry-functions-and-clinical- significance-a-power-point-presentation-2/ 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 37
  38. 38. Thank you 27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 38

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